Antibiotic Lock Solutions in the Prevention of Catheter Related Bacteremia

Summary

To study the efficacy of an antibacterial/anticoagulant solution instilled into the
hemodialysis (HD) catheters after each treatment (“antibiotic lock solution - ALS”) to
prevent catheter related bacteremia (CRB) and to salvage catheters with established CRB.

Description

Scope of the problem. A large number of hemodialysis patients in this country rely on
indwelling tunneled and non-tunneled catheters as vascular access for hemodialysis even
though the K/DOQI guidelines discourage their use. In a study performed by ESRD network 11,
[to which all Michigan dialysis centers submit data] 63% of patients initiated HD with a
catheter as their sole form of vascular access. At 6 months after initiation of HD, 40% of
these patients were still using a catheter. Other studies had shown that the prevalence of
overall catheter use to be around 20% of all accesses.

Catheter associated infection. Current literature indicates that these catheters are
associated with a disproportionate risk for infection, particularly CRB, resulting in high
morbidity, mortality and healthcare expenditure. The ‘epidemic’ of ESRD in this country has
seen an ever increasing reliance on these catheters not only to initiate the HD but also for
long term treatment in those patients who have no other access options. It has been
estimated that intravascular catheters are associated with more than 60,000 cases of
nosocomial bacteremia each year. HD catheters pose a particularly high risk for developing
infections because of their frequent use as well as their long-term use. All indwelling
vascular catheters are colonized by micro-organisms within 24 hours after insertion. The
deposition of biofilm on the external and internal surface of vascular catheters is thought
to play an important role in the colonization process. The biofilm is produced by a
combination of host factors (e.g., fibrinogen, fibrin, fibronectin and extracellular
polysaccharides) and microbial products (e.g., glycocalyx or "slime").

Failure of antibiotics. Systemic antibiotics used to treat bacteremia do not penetrate
catheter lumen and therefore do not eradicate the biofilm, leading to potential treatment
failures and eventual sacrifice of the catheter. Recently published data suggests that using
a combination solution with antibacterial/anticoagulant agents prevents the formation of the
‘biofilm’ in the catheter lumen thereby preventing CRB, as well as salvage the catheters in
cases of established CRB. However, there continues to be a debate on the appropriate
antibacterial agent as well as its optimal concentration, in order to eradicate a wide
variety of organisms. Several other strategies were studied in the past 10 years to prevent
CRB and CRI. These include eradication of nasal Staphylococcal carriage with mupirocin,
using chlorhexidine for catheter hub cleaning and exit site disinfection and using
mupirocin or Polysporin ointments to the exit site along with standard dressing. But
emergence of antibiotic resistance as well as the high costs of administrating these methods
continue to be barriers to their widespread use and cannot be relied upon to manage the high
rate of infection by themselves.

Salvaging catheters. In the past, infected catheters were routinely removed, especially for
Staphylococcus aureus infections, per the CDC guidelines. However, recent small studies
indicate that strategies such as ALS packing or changing catheter over a guide wire can
salvage a significant fraction of these catheters, thereby saving expense and morbidity, and
preserving the site. Thrombotic occlusions and infection are the two most common
complications of the HD catheters, each predisposing to the other. Some studies have shown
that ALS packing has also improved the long-term catheter function by preventing the
formation and propagation of the biofilm. Studying this aspect of catheter maintenance is
also an important outcome for our proposed study.

Antibiotic Lock Solutions. We have identified 10 clinical trials (attached as appendix) in
the published literature describing the results of antibiotic lock therapy for preventing
infections in indwelling vascular catheters. All but one have demonstrated efficacy of ALS
packing. Of the 9 successful trials, only 6 were randomized controlled trials and only 3 of
these were done on HD catheters, as described below.

Need for a prospective study. If we can achieve the same superior results from our study
incorporating the ALS packing strategy, we should be able to assess cost- effectiveness of
using the ALS packing vs. standard approach as has been discussed in previous trials, but
has not been systematically studied. In fact there are insufficient numbers of patients
studies to even perform a meta-analysis. We feel that it is critical to prove the
cost-effectiveness of the new strategy in order for it to be used in a widespread fashion.

The applicant, Anatole Besarab MD, has extensive experience in Nephrology and specifically
in vascular access management. He has published, lectured, and coordinated symposia on
vascular access care and is the current chair of the K/DOQI vascular access workgroup of the
NKF.

This project is conceived for the following reasons.

- The CRB burden in the hemodialysis patients at this institution has reached
overwhelming proportions and needs urgent strategies to counter this ‘epidemic’.
Current management guidelines rely mostly on treatment of established infections but do
not aim at preventing these infections. This kind of economic burden and increased
morbidity/mortality in patients are unacceptable in the current health care
environment. Our study will add to the existing literature in defining the management
guidelines for CRB.

- The Greenfield Health System (GHS) that provides dialysis care to the patients of the
Henry Ford Health System includes several hundreds of patients and would be the ideal
setting to study the proposed intervention. This population also represents a
cross-section of many types of disease severity and number of co-morbid conditions.
Therefore they provide an opportunity to observe the effects on the proposed
intervention in different demographic settings.

- Henry Ford Hospital represents a completely new demography to study the effects of the
proposed intervention. The disease burden with CRB in the population served by this
area is higher than the national average and would be ideal to study the proposed
intervention in more detail.

- The cost effectiveness of using the antibiotic lock therapy has not been well studied
to date and will have a significant impact on the eventual formulation of treatment
guidelines. In the setting of current economic burden in the health care industry,
study of this issue is vital and timely. The vision of a simple, cheap intervention
that can result in savings of millions of dollars is central to this study.

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Medical and Biotech [MESH] Definitions

Atp Citrate (pro-s)-lyase

An enzyme that, in the presence of ATP and COENZYME A, catalyzes the cleavage of citrate to yield acetyl CoA, oxaloacetate, ADP, and ORTHOPHOSPHATE. This reaction represents an important step in fatty acid biosynthesis. This enzyme was formerly listed as EC 4.1.3.8.

Citrate (si)-synthase

Enzyme that catalyzes the first step of the tricarboxylic acid cycle (CITRIC ACID CYCLE). It catalyzes the reaction of oxaloacetate and acetyl CoA to form citrate and coenzyme A. This enzyme was formerly listed as EC 4.1.3.7.

Minocycline

A TETRACYCLINE analog, having a 7-dimethylamino and lacking the 5 methyl and hydroxyl groups, which is effective against tetracycline-resistant STAPHYLOCOCCUS infections.

Insulysin

An enzyme the catalyzes the degradation of insulin, glucagon and other polypeptides. It is inhibited by bacitracin, chelating agents EDTA and 1,10-phenanthroline, and by thiol-blocking reagents such as N-ethylmaleimide, but not phosphoramidon. (Eur J Biochem 1994;223:1-5) EC 3.4.24.56.

Diethylcarbamazine

An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa.

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